Implantable medical devices fabricated from polymers with radiopaque groups

ABSTRACT

Inplantable medical devices fabricated from radiopaque polymers are disclosed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to implantable medical devices fabricated frompolymers with radiopaque polymers.

2. Description of the State of the Art

This invention relates to radially expandable endoprostheses, which areadapted to be implanted in a bodily lumen. An “endoprosthesis”corresponds to an artificial device that is placed inside the body. A“lumen” refers to a cavity of a tubular organ such as a blood vessel.

A stent is an example of such an endoprosthesis. Stents are generallycylindrically shaped devices, which function to hold open and sometimesexpand a segment of a blood vessel or other anatomical lumen such asurinary tracts and bile ducts. Stents are often used in the treatment ofatherosclerotic stenosis in blood vessels. “Stenosis” refers to anarrowing or constriction of the diameter of a bodily passage ororifice. In such treatments, stents reinforce body vessels and preventrestenosis following angioplasty in the vascular system. “Restenosis”refers to the reoccurrence of stenosis in a blood vessel or heart valveafter it has been treated (as by balloon angioplasty, stenting, orvalvuloplasty) with apparent success.

The treatment of a diseased site or lesion with a stent involves bothdelivery and deployment of the stent. “Delivery” refers to introducingand transporting the stent through a bodily lumen to a region, such as alesion, in a vessel that requires treatment. “Deployment” corresponds tothe expanding of the stent within the lumen at the treatment region.Delivery and deployment of a stent are accomplished by positioning thestent about one end of a catheter, inserting the end of the catheterthrough the skin into a bodily lumen, advancing the catheter in thebodily lumen to a desired treatment location, expanding the stent at thetreatment location, and removing the catheter from the lumen. The stentmay be visualized during delivery and deployment using X-Ray fluoroscopyif it contains radiopaque materials.

In the case of a balloon expandable stent, the stent is mounted about aballoon disposed on the catheter. Mounting the stent typically involvescompressing or crimping the stent onto the balloon. The stent is thenexpanded by inflating the balloon. The balloon may then be deflated andthe catheter withdrawn. In the case of a self-expanding stent, the stentmay be secured to the catheter via a constraining member such as aretractable sheath or a sock. When the stent is in a desired bodilylocation, the sheath may be withdrawn which allows the stent toself-expand.

The stent must be able to satisfy a number of mechanical requirements.First, the stent must be capable of withstanding the structural loads,namely radial compressive forces, imposed on the stent as it supportsthe walls of a vessel. Therefore, a stent must possess adequate radialstrength. Radial strength, which is the ability of a stent to resistradial compressive forces, is due to strength and rigidity around acircumferential direction of the stent. Radial strength and rigidity,therefore, may also be described as, hoop or circumferential strengthand rigidity.

Once expanded, the stent must adequately maintain its size and shapethroughout its service life despite the various forces that may come tobear on it, including the cyclic loading induced by the beating heart.For example, a radially directed force may tend to cause a stent torecoil inward. Generally, it is desirable to minimize recoil. Inaddition, the stent must possess sufficient flexibility to allow forcrimping, expansion, and cyclic loading. Longitudinal flexibility isimportant to allow the stent to be maneuvered through a tortuousvascular path and to enable it to conform to a deployment site that maynot be linear or may be subject to flexure. Finally, the stent must bebiocompatible so as not to trigger any adverse vascular responses.

The structure of a stent is typically composed of scaffolding thatincludes a pattern or network of interconnecting structural elementsoften referred to in the art as struts or bar arms. The scaffolding canbe formed from wires, tubes, or sheets of material rolled into acylindrical shape. The scaffolding is designed so that the stent can beradially compressed (to allow crimping) and radially expanded (to allowdeployment). A conventional stent is allowed to expand and contractthrough movement of individual structural elements of a pattern withrespect to each other.

Additionally, a medicated stent may be fabricated by coating the surfaceof either a metallic or polymeric scaffolding with a polymeric carrierthat includes an active or bioactive agent or drug. Polymericscaffolding may also serve as a carrier of an active agent or drug.

Furthermore, it may be desirable for a stent to be biodegradable. Inmany treatment applications, the presence of a stent in a body may benecessary for a limited period of time until its intended function of,for example, maintaining vascular patency and/or drug delivery isaccomplished. Therefore, stents fabricated from biodegradable,bioabsorbable, and/or bioerodable materials such as bioabsorbablepolymers should be configured to completely erode only after theclinical need for them has ended.

Potential problems with polymeric implantable medical devices, such asstents, include insufficient toughness, slow degradation rate, andlimited shelf life due to physical aging and stress relaxation. Anotherproblem with polymeric stents is that polymer tend to be radiolucent,and thus cannot be visualized with X-ray fluoroscopy.

SUMMARY OF THE INVENTION

Various embodiments of the present invention include a stent formed froma biodegradable polymer material, wherein radiopaque functional groupsare chemically bonded to at least some of polymers of the polymermaterial.

Further embodiments of the present invention include an implantablemedical device comprising structural elements fabricated at least inpart from a polymer blend comprising: a biodegradable matrix polymerblended with biodegradable linear block copolymers, the linear blockcopolymers having a discrete phase segment and a continuous phasesegment, wherein the discrete phase segment is immiscible with thematrix polymer such that discrete phase segments form a discrete phasewithin the matrix polymer, wherein the continuous phase segment ismiscible with the matrix polymer, wherein radiopaque functional groupsare chemically bonded to the discrete phase segments, the continuousphase segments, or both.

Additional embodiments of the present invention include an implantablemedical device comprising structural elements fabricated at least inpart from a polymer blend comprising: a biodegradable matrix polymerblended with biodegradable star-block copolymers, the star-blockcopolymers having at least three arms, wherein the arms include innersegments and outer segments, the inner segments being immiscible withthe matrix polymer and forming a discrete phase within the matrixpolymer, wherein the outer segments are miscible with the matrixpolymer, wherein radiopaque functional groups are chemically bonded tothe inner segments or the outer segments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a view of a stent.

FIG. 2 depicts an unbranched polymer with radiopaque functional groups.

FIG. 3 depicts a star polymer with radiopaque functional groups.

FIG. 4A depicts a section of a segment of a strut from the stentdepicted in FIG. 1.

FIG. 4B depicts a microscopic schematic view of a portion of a segmentof a strut as depicted in FIG. 4A

FIG. 5 depicts a linear block copolymer with radiopaque functionalgroups.

FIG. 6 depicts a star-block copolymer having four arms with radiopaquefunctional groups.

DETAILED DESCRIPTION OF THE INVENTION

Various embodiments of the present invention include an implantablemedical device formed from a polymeric material including a polymerhaving radiopaque functional groups. In some embodiments, the radiopaquefunctional groups provide sufficient radiopacity to the polymericmaterial so that the device can be imaged by X-ray fluoroscopy.

As used herein, an “implantable medical device” includes, but is notlimited to, self-expandable stents, balloon-expandable stents,stent-grafts, other expandable tubular devices for various bodily lumenor orifices, implantable cardiac pacemakers and defibrillators, leadsand electrodes for the preceding, vascular grafts, grafts, artificialheart valves, and cerebrospinal fluid shunts. An,implantable medicaldevice can be designed for the localized delivery of a therapeuticagent. A medicated implantable medical device may be constructed bycoating the device or substrate with a coating material containing atherapeutic agent. The substrate of the device may also contain atherapeutic agent.

FIG. 1 depicts a view of a stent 100. In some embodiments, a stent mayinclude a pattern or network of interconnecting structural elements 105.Stent 100 may be formed from a tube (not shown). The pattern ofstructural elements 105 can take on a variety of patterns. Thestructural pattern of the device can be of virtually any design. Theembodiments disclosed herein are not limited to stents or to the stentpattern illustrated in FIG. 1. The embodiments are easily applicable toother patterns and other devices. The variations in the structure ofpatterns are virtually unlimited. A stent such as stent 100 may befabricated from a tube by forming a pattern with a technique such aslaser cutting or chemical etching.

An implantable medical device can be made partially or completely from abiodegradable, bioabsorbable, biostable polymer, or a combinationthereof. A polymer for use in fabricating an implantable medical devicecan be biostable, bioabsorbable, biodegradable or bioerodable. Biostablerefers to polymers that are not biodegradable. The terms biodegradable,bioabsorbable, and bioerodable are used interchangeably and refer topolymers that are capable of being completely degraded and/or erodedwhen exposed to bodily fluids such as blood and can be graduallyresorbed, absorbed, and/or eliminated by the body. The processes ofbreaking down and absorption of the polymer can be caused by, forexample, hydrolysis and metabolic processes.

There are several characteristics that are important for implantablemedical devices, such as stents, including high radial strength, goodfracture toughness, fast degradation, and radiopacity. Some polymersthat may be suitable for use in implantable medical devices havepotential shortcomings with respect to these characteristics, inparticular, fracture toughness and degradation rate.

Some crystalline or semi-crystalline polymers that are glassy or have aTg above body temperature are particularly attractive as stent materialsdue to their strength and stiffness. The toughness of such polymers canbe lower than desired, in particular, for use in stent applications. Forexample, polymers such as PLLA are stiff and strong, but tend to bebrittle under physiological conditions. Physiological conditions referto conditions that an implant is exposed to within a human body.Physiological conditions include, but are limited to, human bodytemperature, approximately 37° C. These polymers can exhibit a brittlefracture mechanism at these conditions in which there is little or noplastic deformation prior to failure. As a result, a stent fabricatedfrom such polymers can have insufficient toughness for the range of useof a stent.

Furthermore, some biodegradable polymers have a degradation rate that isslower than desired for certain stent treatments. As a result, thedegradation time of a stent made from such polymers can be longer thandesired. For example, a stent made from a semicrystalline polymer suchas PLLA can have a degradation time between about two and three years.In some treatment situations, a shorter degradation time is desirable,for example, less than 6 months or a year.

Additionally, polymers generally do not possess sufficient radiographicdensity to be easily imaged by fluoroscopy. Since a device such as astent also has specific mechanical requirements, it is important thatrendering a polymeric stent sufficiently radiopaque for imaging does notsignificantly impact its mechanical behavior. One way to improve theimaging of polymeric materials is to incorporate radiopaque fillermaterials into a polymeric material to enhance radiographic density.However, such materials may adversely affect the mechanical propertiesof the polymer, such as strength and toughness.

An alternative to filler materials is to fabricate a stent from polymershaving radiopaque dye or functional group covalently bonded to thepolymer backbone end groups. It is believed that the radiopaque densityof the stent can be enhanced by the radiopaque functional groups withoutsignificantly impacting mechanical properties of the stent. Embodimentsof the present invention include a stent formed from a biodegradablepolymer material in which radiopaque functional groups are chemicallybonded to at least some of polymers of the polymer material.

A radiopaque functional group can be any chemical group or species thatcan be bonded to a polymer backbone that increases or enhances theradiographic density of the polymer. Representative examples ofradiopaque functional groups include iodine, triuodobenzoyl chloride,and triidobenzoic acid.

A radiopaque functional group can be added to the end of a polymer oralong the backbone of the polymer. A radiopaque functional group can beadded to the end of an aliphatic polyester through an esterificationreaction. In this reaction, a radiopaque group is substituted for aproton of a hydroxyl end group. Radiopaque agents such as triethyl amineand truidobenzoyl chloride are added to a polymer solution to allow anesterification reaction to occur. Exemplary synthesis schemes areprovided herein.

Additionally, radiopaque groups can be covalently bonded to the backboneof some aliphatic polyesters. Biomaterials, 27 (2006) 4948-4954. It hasbeen shown that iodine can be added to the backbone poly(caprolactone)by the removal of a proton of the methylene group in a position of theester carbonyl. It is believed that such a scheme can be generallyapplied to aliphatic polyesters having such methylene groups. Theseinclude, but are limited to, poly(tetramethyl carbonate) (PTMC),poly(4-hydroxy butyrate), and polydioxanone.

Exemplary synthesis schemes are provided herein. In some embodiments, amajority of stent can be formed from an unbranched biodegradablepolymer. In such embodiments, the unbranched polymer can be asemcrystalline polymer such as poly(L-lactide) (PLLA), polyglycolide(LPLG), poly(tetramethyl carbonate) (PTMC), poly(4-hydroxy butyrate),polydioxanone, and copolymers thereof, or some other hydrolyticallydegradable semicrystalline polymer. The radiopaque functional groups maybe chemically bonded to one or more of the ends of at least some of thepolymers of the polymer material. Additionally or alternatively, theradiopaque functional groups can be chemically bonded along chains of atleast some of the polymers of the polymer material. For example, apoly(lactide-co-caprolactone) copolymer can have radiopaque groups alongthe backbone bonded to the caprolactone groups. A polymer can include anamount of radiopaque functional groups that provide a sufficient degreeof radiopacity to image the stent.

FIG. 2 depicts a schematic illustration of an unbranched polymer 150with chemically bonded radiopaque functional groups. Polymer 150 hasradiopaque groups 154 along its backbone 152 and radiopaque groups 156endcapping backbone 152.

In further embodiments, a stent can be formed at least in part of starpolymers. A star polymer is a polymer with at least three polymer chainsor arms radiating from a center. The radiopaque functional groups can bechemically bonded to one or more of the ends of the arms of the starpolymers. Additionally or alternatively, the radiopaque functionalgroups can be bonded along the chains of the arms of the star polymer.In an embodiment, a stent can be formed at least in part ofbiodegradable polymer material that is a blend of an unbranched polymerand a star copolymer with radiopaque functional groups chemically bondedto the star copolymer.

FIG. 3 depicts a star polymer 160 chemically bonded with radiopaquefunctional groups. Star polymer 160 has four arms 162. Radiopaque groups164 are chemically bonded along the chain of arms 162. Radiopaque groups166 endcap arms 162. Radiopaque functional groups can be added to theunbranched or star polymers through the synthesis schemes describedabove.

Further embodiments of the present invention address all three of thepotential shortcomings discussed above, inadequate toughness, slowdegradation rate, and lack of radiopacity. One way to form a tougherpolymeric material from a brittle polymer is to form a polymer blendincluding the brittle polymer and another polymer that has a higherfracture toughness than the brittle polymer. The higher toughnesspolymer should also be immiscible with or form a separate phase from thebrittle polymer. For example, the higher toughness polymer can be adispersed phase such that it forms discrete phase domains within thematrix polymer. The fracture toughness of a device is increased sincethe discrete phase can absorb energy arising from stress imparted to adevice. To ensure good energy transfer between interfaces of the phases,it is important that there be sufficient bonding or adhesion between thephases. See, Y. Wang, etc. Journal of Polymer Science Part A: PolymerChemistry, 39, 2001, 2755-2766. The dispersed phase should beinterfacially compatible to reduce or eliminate formation of voids whenthe polymer blend is under stress, for example, when a stent isexpanded.

Such further embodiments of the present invention include an implantablemedical device fabricated at least in part from a polymer blend having adiscrete or dispersed phase within a continuous phase. The polymer blendincludes a matrix polymer blended with a block copolymer. At least oneof the blocks, a discrete phase block, forms a discrete phase within thecontinuous matrix polymer phase since it is immiscible with the matrixpolymer. At least another block, which is miscible with the matrixpolymer, is within the continuous phase and provides interfacial bondingbetween the phases. Thus, these embodiments enhance the fracturetoughness of a polymer for use in a stent. The block copolymer can bedispersed throughout the matrix polymer so that there is a plurality ofdiscrete phase regions within the blend.

In some embodiments, the discrete phase can be faster degrading that thematrix polymer, and thus can provide a sufficiently fast degradationrate. The faster degradation can be due at least in part to theamorphous structure of the discrete phase since the diffusion rate offluids through an amorphous structure is generally faster than through acrystalline structure.

In some embodiments, the matrix polymer has a high rigidity and arelatively low fracture toughness at physiological conditions. Suchpolymers may be selected as a matrix polymer for stent applicationssince such rigid polymers can support the walls of a vessel. Thediscrete phase segments can have a higher fracture toughness atphysiological conditions, which can increase the toughness of thepolymer blend. The continuous phase segments can improve adhesionbetween the continuous and discrete phases to facilitate energy transferbetween the phases.

FIG. 4A depicts a section of a segment 110 of strut 105 from the stentdepicted in FIG. 1. FIG. 4B depicts a microscopic schematic view of aportion 140 of segment 110 of a strut as depicted in FIG. 4A. Portion140 includes a plurality of discrete phase regions 200 dispersed withina continuous phase 210. L_(D) is a characteristic dimension of discretephase region 200.

It is believed that when a device is placed under stress, the discretephase tends to absorb energy when a fracture starts to propagate througha structural element. Crack propagation through the continuous phase maythen be reduced or inhibited. As a result, fracture toughness of thepolymer blend, and thus, the implantable medical device tends to beincreased. The continuous phase segments of the block copolymer increasethe adhesion between the discrete phase regions and the continuousphase. Thus, the discrete phase segments facilitate energy transferbetween interfaces of the phases. Without the anchoring or adhesionprovided by the continuous phase segments, a propagating crack may goaround the discrete phase, reducing the effectiveness of the discretephase in absorbing energy imparted to a device.

Generally, it is desirable for the discrete phase regions to beuniformly or substantially uniformly dispersed throughout the polymermatrix to facilitate the increase in toughness. The more dispersed thediscrete phase regions, the greater is the increase in toughness.Additionally, the increase in toughness is related to the size of thediscrete phase. Both the degree of dispersion and discrete phase sizecan be controlled by the length or molecular weight of the discretephase inner segments. The characteristic length of a discrete phase canbe 1 nm to 100 nm, 100 nm to 500 nm, 500 nm to 1,000 nm, 1000 nm to10,000 nm, or greater than 10,000 nm. The molecular weight of the innersegments can be adjusted to obtain a desired characteristic length. Forexample, the molecular weight of the inner segments can be 10-50 kD,50-100 kD, or higher than 100 kD.

In some embodiments, the block copolymer can be linear. In suchembodiments, a biodegradable matrix polymer is blended withbiodegradable linear block copolymers. Each of the linear blockcopolymers have one discrete phase segment and one continuous phasesegment. The discrete phase segments form the discrete phase and thecontinuous phase segments are within the continuous matrix phase.

In some embodiments, the block copolymer can be a star block copolymer.In such embodiments, the polymer blend includes a matrix polymer blendedwith a star-block copolymer having at least three arms. In anembodiment, the arms include inner core segments that are discrete phasesegments and outer segments that are continuous phase segments. Thediscrete phase inner segments are immiscible with the outer segments andthe matrix polymer. The discrete phase inner segments form a discretephase with the continuous phase which includes the matrix polymer andthe outer segments.

In general, the continuous phase segments can be selected so that theyare miscible with the matrix polymer. In some embodiments, thecontinuous phase segments can be the same chemical composition as thematrix polymer. For example, a polymer blend with a PLLA matrix polymercan have PLLA continuous phase segments.

In some embodiments, the discrete phase segments of a block copolymerinclude units that form polymers having a higher fracture toughness atphysiological conditions than a rigid matrix polymer, such as PLLA. Thediscrete phase segments can form a discrete phase that is more flexibleand has a lower modulus than the matrix polymer of the continuous phase.The matrix polymer can be selected to have a Tg above body temperature,so that the matrix polymer remains rigid after implantation. Generally,the discrete phase segments may be selected that have a Tg below bodytemperature. In one embodiment, the discrete phase segments of the blockpolymer can be a rubbery or elastomeric polymer. An “elastomeric” or“rubbery” polymer refers to a polymer that exhibits elastic deformationthrough all or most of a range of deformation. In some embodiments, thediscrete phase can be substantially or completely amorphous.

Biodegradable polymers having a relatively high fracture toughness atbody temperature include, but are not limited to, polycaprolactone(PCL), poly(tetramethyl carbonate) (PTMC), poly(4-hydroxy butyrate), andpolydioxanone. Thus, some embodiments of the discrete phase segments ofthe block polymer can include caprolactone (CL), tetramethyl carbonate(TMC), 4-hydroxy butyrate, dioxanone units, or a combination thereof.

Radiopaque functional groups can be chemically bonded to the discretephase segments or the continuous phase segments of the linear or starblock copolymers to provide radiopacity to the device. The radiopaquefunctional groups can be bonded to the end groups of the continuous anddiscrete phase segments of the linear block copolymer. The radiopaquefunctional groups can also be bonded to the end groups of the continuousphase segments of the star block copolymer.

Additionally, the radiopaque functional groups can be bonded along thebackbone of the continuous and discrete phase segments. For example, thecontinuous phase segments can include units such as CL, TMC, 4-hydroxybutyrate, and dioxanone that allow substitution of the radiopaquefunctional group for the proton of the methylene group in α position ofthe ester carbonyl. Further, such units can be included in thecontinuous phase segments to allow the same substitution.

FIG. 5 depicts a linear block copolymer 168 with a discrete phasesegment 169 and a continuous phase segment 170. Radiopaque functionalgroups 175 are bonded along discrete phase segments, continuous phasesegments, and the ends of both segments FIG. 6 depicts a star-blockcopolymer 172 having four arms 174 with radiopaque functional groups175. Arms 174 have discrete phase inner segments 176 (shown as brokenlines) and continuous phase outer segments 178. Radiopaque functionalgroups 175 are bonded along inner segments, outer segments, and the endsof the outer segments.

In one embodiment, a polymer blend can have a PLLA matrix polymer withP(CL-co-TMC)-b-PLLA linear or star block copolymer dispersed within thePLLA matrix. The discrete phase segments are P(CL-co-TMC) and thecontinuous phase segments are PLLA. The PLLA continuous phase segmentsof the block copolymer are included within the continuous matrix phase.The PLLA continuous phase segments binds the discrete phase with thecontinuous phase, facilitating the increase in the fracture toughnessprovided to the polymer blend. In exemplary embodiments, the polymerblend can include about 1-30 wt %, or more narrowly, 5-20 wt % of ablock copolymer and about 75-95 wt % of matrix polymer.

In additional embodiments, the block copolymer can include units in thediscrete phase segments with characteristics that tend to increase thedegradation rate of the blend. For example, the discrete phase innersegments can include units that are more hydrophilic than the matrixpolymer. The discrete phase inner segments can also have units that aremore hydrolytically active than the matrix polymer. These twocharacteristics increase the moisture content of the polymer blend whichincreases the degradation rate of the blend. Additionally, the discretephase segments can also have units that have acidic and hydrophilicdegradation products. Since the rate of the hydrolysis reaction tends toincrease as the pH decreases, acidic degradation products can increasethe degradation rate of the blend and the device. Glycolide (GA) units,for example, have acidic degradation products which can increase thedegradation rate of a polymer blend when included in a discrete phasesegment.

In some embodiments, the discrete phase segments can include units thatincrease the fracture toughness (toughness-enhancing units) of thepolymer blend and units that have one or more of the characteristicsthat increase degradation rate mentioned above (fast degrading units).In an exemplary embodiment, the discrete phase segments can include bothCL and GA units. In particular, the discrete phase inner segments can bepoly(glycolide-co-ε-caprolactone) (P(GA-co-CL)). P(GA-co-CL) discretephase segments can have alternating or random GA and CL units.

An exemplary block copolymer for blending with PLLA can includePLLA-b-P(CL-co-GA). The faster degrading GA units can increase thedegradation rate of the polymer blend by increasing the equilibriumwater content and penetration into the structural element. Degradationof GA units further increases the degradation rate due to the acidic andhydrophilic degradation products.

In some embodiments, the flexibility and degradation rate of thediscrete phase segments can be adjusted by the ratio of fast degradingand toughness-enhancing units. As the ratio of CL, for example,increases in P(GA-co-CL) segments, the a block copolymer becomes moreflexible and tougher. The Tg of the discrete phase segments can be tunedto a desired value by adjusting the ratio of component monomers. Forexample, the Tg of the discrete phase may be engineered to be less thana body temperature to provide a more flexible discrete phase underphysiological conditions. Additionally, the degradation rate of thediscrete phase segments, and thus the blend, can be increased byincreasing the fraction of GA in the discrete phase segments. Inexemplary embodiments, the P(GA-co-CL) segments can have up to 1 wt %, 5wt %, 20 wt %, 50 wt %, 70 wt %, 80 wt %, or 90 wt % GA units.

In an exemplary embodiment, a polymer blend can have a PLLA matrixpolymer with P(GA-co-CL)-b-PLLA block copolymer dispersed within thePLLA matrix. The discrete phase segments are P(GA-co-CL) and thecontinuous phase segments are PLLA. The PLLA continuous phase segmentsof the block copolymer phase separate into the PLLA matrix of thecontinuous matrix phase. The PLLA continuous phase segment binds thediscrete phase with the continuous phase, facilitating the increase inthe fracture toughness provided to the polymer blend. In exemplaryembodiments, the polymer blend can include about 1-30 wt %, or morenarrowly, 5-20 wt % of block copolymer and about 75-95 wt % of matrixpolymer.

In further embodiments, the matrix polymer can be a copolymer. In someembodiments, a matrix copolymer can be composed of a primary functionalgroup and at least one additional secondary functional group. Thecopolymer matrix may be a random copolymer including the primaryfunctional group and at least one additional secondary functional group.In an embodiment, the copolymer with at least one secondary functionalgroup can have a higher degradation rate than a homopolymer composed ofthe primary functional group. A secondary functional group can have agreater affinity for water or be more hydrolytically active than thesecondary functional group. The secondary functional group can haveacidic and hydrophilic degradation products that enhance the degradationof the matrix polymer and polymer blend. Additionally, a copolymermatrix may have lower crystallinity, which also tends to increasedegradation rate. In some exemplary embodiments, the weight percent ofthe secondary functional group in the copolymer can have up to 1%, 5%,10%, 15%, 30%, 40%, or, at least about 50%. In some embodiments, theweight percent of the secondary function group can be greater than 50%.

In an exemplary embodiment, the matrix copolymer can bepoly(L-lactide-co-glycolide) (LPLG). The primary functional group can beL-lactide and the secondary functional group can be GA. The weightpercent of the GA in the copolymer can be up to 1%, 5%, 10%, 15%, 30%,40%, or at least about 50%. In certain exemplary embodiments, the weightpercent of the GA group can be adjusted so that the degradation time ofa stent, can be less than 18 months, 12 months, 8 months, 5 months, 3months, or more narrowly, less than 3 months.

Additionally, the continuous phase segments of the block copolymer canbe selected so that the continuous phase segments are miscible with thematrix copolymer. In one embodiment, the continuous phase segment canhave the same chemical composition as the matrix copolymer. In anotherembodiment, the continuous phase segment can have a compositiondifferent from the matrix copolymer, but close enough so that thecontinuous phase segment is miscible with the matrix polymer. In anotherembodiment, the continuous phase segments can have a compositiondifferent from the matrix polymer with the continuous phase segmentsbeing miscible with the matrix polymer.

In another exemplary embodiment, a polymer blend can have an LPLG matrixpolymer with P(CL-co-TMC)-b-LPLG block copolymer dispersed within theLPLG matrix.

The discrete phase segments are P(CL-co-TMC) and the continuous phasesegments are LPLG. The LPLG continuous phase segments of the star-blockcopolymer phase separate into the LPLG matrix of the continuous matrixphase. The LPLG discrete phase segment binds the discrete phase with thecontinuous phase, facilitating the increase in the fracture toughnessprovided to the polymer blend. In exemplary embodiments, the polymerblend can include about 1-30 wt %, or more narrowly, 5-20 wt % of ablock copolymer and about 75-95 wt % of matrix polymer.

In further exemplary embodiments, a polymer blend can have an LPLGmatrix polymer with P(GA-co-CL)-b-LPLG block copolymer dispersed withinthe LPLG matrix. The discrete phase segments are P(GA-co-CL) and thecontinuous phase segments are LPLG.

Linear and star-block copolymers, such as P(CL-co-TMC)-b-PLLA,P(GA-co-CL)-b-PLLA, P(CL-co-TMC)-b-LPLG, or P(GA-co-CL)-b-LPLG, can beformed by solution-based polymerization. Radiopaque functional groupscan be added to the copolymers after formation of the copolymers. Aradiopaque compound such as triidobenzoyl chloride can be added to asolution containing the formed copolymers to allow an esterificationreaction to proceed which chemically bonds the radiopaque functionalgroups to the copolymer. Other methods of forming the block copolymersare also possible, such as, without limitation, melt phasepolymerization.

One embodiment of the solution polymerization involves forming thediscrete phase segments first and then the continuous phase segments.The discrete phase monomers are combined with an appropriate solventalong with an appropriate initiator and catalyst to form the discretephase segments. The continuous phase monomers and catalyst are thenadded to the solution to form the continuous phase blocks.

For example, to prepare P(GA-co-CL)-b-PLLA linear block copolymer,P(GA-co-CL) segments are formed first by mixing GA and CL monomers witha xylene solvent to form a solution which includes dodecanol asinitiator and stannous octoate as catalyst. L-lactide monomers can thenbe added to the solution. The L-lactide monomers react with P(GA-co-CL)to form P(GA-co-CL)-b-PLLA.

Biodegradable multi-arm star-block copolymers can be synthesized throughring opening polymerization. J. Biomater. Sci. Polymer Edn., Vol. 17,2006, 615-630. To prepare P(CL-co-TMC)-b-PLLA star-block copolymer, aprecursor P(CL-co-TMC) star copolymer may be prepared first by solutionpolymerization. The P(CL-co-TMC) star copolymer is then employed as amacro-initiator to initiate the polymerization of L-lactide monomers toform the PLLA outer segments. Specifically, P(CL-co-TMC) star copolymeris formed first by mixing glycerol initiator, stannous octoate catalyst,CL units, and TMC units with a xylene solvent to form a solution. In thesolution, the glycerol, CL, and TMC units react to form a three armP(GA-co-CL) star copolymer. L-lactide monomers are added to the solutionand react with P(CL-co-TMC) star copolymer to form P(CL-co-TMC)-b-PLLAstar-block copolymer.

To prepare P(GA-co-CL)-b-PLLA star-block copolymer, precursorP(GA-co-CL) star copolymer is formed first in a solution containing asolvent with GA units, CL units, pentaerythritol initiator, and stannousoctoate catalyst. L-lactide monomers are then added to the solution toreact with P(GA-co-CL) star copolymer to form P(GA-co-CL)-b-PLLA starblock copolymer.

To prepare P(CL-co-TMC)-b-LPLG star-block copolymer, precursorP(CL-co-TMC) star copolymer is formed first in a solution containing asolvent with CL units, TMC units, glycerol initiator, and stannousoctoate catalyst. L-lactide and GA units are then added to the solutionto react with P(CL-co-TMC) star copolymer to form P(CL-co-TMC)-b-LPLGstar-block copolymer.

Following each of these synthesis schemes, radiopaque functional groupscan be added to the synthesized block copolymers as described above andin the examples below.

The solvent(s) can be selected so that the block copolymer precursor issoluble in the solvent(s) to enable the precursor copolymer tocopolymerize with continuous phase segment units.

In other embodiments, block copolymers can be formed by reactingprecursor discrete phase segments swollen with a solvent that containcontinuous phase units. The precursor copolymer is swollen by a solventafter it is formed so that it can react with continuous phase units. Oneof skill in the art can select a solvent that swells but does notdissolve the precursor segments In one embodiment, the solvent for usein synthesizing the copolymer is devoid of alcohol functional groups.Such alcohol groups may act as initiators for chain growth in thepolymer. Solvents used to synthesize the star-block copolymer include,but are not limited to, chloroform, toluene, xylene, and cyclohexane.

In some embodiments, the polymer blend of the matrix polymer and theblock copolymer can be formed by solution blending, melt blending, or acombination thereof. The matrix polymer can be co-extruded with thepolymer blend. The extruded polymer blend may be formed into a polymerconstruct, such as a tube or sheet which can be rolled or bonded to forma construct such as a tube. An implantable medical device may then befabricated from the construct. For example, a stent can be fabricatedfrom a tube by laser machining a pattern in to the tube. In anotherembodiment, a polymer construct may be formed from the polymer blendusing an injection molding apparatus.

In some embodiments, the radiopacity of a stent can be enhanced byincluding a radiopaque layer in addition to a substrate or scaffoldingcomposed primarily or completely of the polymer blend described herein.In such embodiments, the additional radiopaque layer can be an outerlayer. The additional layer can be composed primarily or completely ofblock copolymer with radiopaque functional groups. The polymer blendlayer can serve as a substrate or scaffolding that provides structuralsupport and the block copolymer layer can serve primarily as aradiopaque layer.

In an embodiment, a two layer stent can be formed from a two layer tubewith one layer being the polymer blend and another layer being the blockcopolymer with radiopaque functional groups. Such a tube can be formedthrough coextrusion of the polymer blend with a block copolymer. Two ormore additional radiopaque layers are also possible. In otherembodiments, the additional radiopaque layer can be a coating over ascaffolding or substrate composed of the polymer blend.

In general, representative examples of polymers that may be used inembodiments of the present invention include, but are not limited to,poly(N-acetylglucosamine) (Chitin), Chitosan, poly(hydroxyvalerate),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,poly(glycolic acid), poly(glycolide), poly(L-lactic acid),poly(L-lactide), poly(D,L-lactic acid), poly(L-lactide-co-glycolide);poly(D,L-lactide), poly(caprolactone), poly(trimethylene carbonate),polyethylene amide, polyethylene acrylate, poly(glycolicacid-co-trimethylene carbonate), co-poly(ether-esters) (e.g. PEO/PLA),polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose,starch, collagen and hyaluronic acid), polyurethanes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers other than polyacrylates,vinyl halide polymers and copolymers (such as polyvinyl chloride),polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidenehalides (such as polyvinylidene chloride), polyacrylonitrile, polyvinylketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters(such as polyvinyl acetate), acrylonitrile-styrene copolymers, ABSresins, polyamides (such as Nylon 66 and polycaprolactam),polycarbonates, polyoxymethylenes, polyimides, polyethers,polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate,cellulose butyrate, cellulose acetate butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, and carboxymethylcellulose.

Additional representative examples of polymers that may be especiallywell suited for use in embodiments of the present invention includeethylene vinyl alcohol copolymer (commonly known by the generic nameEVOH or by the trade name EVAL), poly(butyl methacrylate),poly(vinylidene fluoride-co-hexafluororpropene) (e.g., SOLEF 21508,available from Solvay Solexis PVDF, Thorofare, N.J.), polyvinylidenefluoride (otherwise known as KYNAR, available from ATOFINA Chemicals,Philadelphia, Pa.), ethylene-vinyl acetate copolymers, and polyethyleneglycol.

For the purposes of the present invention, the following terms anddefinitions apply:

For the purposes of the present invention, the following terms anddefinitions apply:

The “glass transition temperature,” Tg, is the temperature at which theamorphous domains of a polymer change from a brittle vitreous state to asolid deformable, ductile, or rubbery state at atmospheric pressure. Inother words, the Tg corresponds to the temperature where the onset ofsegmental motion in the chains of the polymer occurs. When an amorphousor semicrystalline polymer is exposed to an increasing temperature, thecoefficient of expansion and the heat capacity of the polymer bothincrease as the temperature is raised, indicating increased molecularmotion. As the temperature is raised the actual molecular volume in thesample remains constant, and so a higher coefficient of expansion pointsto an increase in free volume associated with the system and thereforeincreased freedom for the molecules to move. The increasing heatcapacity corresponds to an increase in heat dissipation throughmovement. Tg of a given polymer can be dependent on the heating rate andcan be influenced by the thermal history of the polymer. Furthermore,the chemical structure of the polymer heavily influences the glasstransition.

“Stress” refers to force per unit area, as in the force acting through asmall area within a plane. Stress can be divided into components, normaland parallel to the plane, called normal stress and shear stress,respectively. True stress denotes the stress where force and area aremeasured at the same time. Conventional stress, as applied to tensionand compression tests, is force divided by the original gauge length.

“Strength” refers to the maximum stress along an axis which a materialwill withstand prior to fracture. The ultimate strength is calculatedfrom the maximum load applied during the test divided by the originalcross-sectional area.

“Modulus” may be defined as the ratio of a component of stress or forceper unit area applied to a material divided by the strain along an axisof applied force that results from the applied force at very low strainwhere the stress-strain curve is linear. For example, a material hasboth a tensile and a compressive modulus. A material with a relativelyhigh modulus tends to be stiff or rigid. Conversely, a material with arelatively low modulus tends to be flexible. The modulus of a materialdepends on the molecular composition and structure, temperature of thematerial, amount of deformation, and the strain rate or rate ofdeformation. For example, below its Tg, a polymer tends to be brittlewith a high modulus. As the temperature of a polymer is increased frombelow to above its Tg, its modulus decreases.

“Strain” refers to the amount of elongation or compression that occursin a material at a given stress or load.

“Elongation” may be defined as the increase in length in a materialwhich occurs when subjected to stress. It is typically expressed as apercentage of the original length.

“Toughness” is the amount of energy absorbed prior to fracture, orequivalently, the amount of work required to fracture a material. Onemeasure of toughness is the area under a stress-strain curve from zerostrain to the strain at fracture. Thus, a brittle material tends to havea relatively low toughness.

“Solvent” is defined as a substance capable of dissolving or dispersingone or more other substances or capable of at least partially dissolvingor dispersing the substance(s) to form a uniformly dispersed solution atthe molecular- or ionic-size level at a selected temperature andpressure. The solvent should be capable of dissolving at least 0.1 mg ofthe polymer in 1 ml of the solvent, and more narrowly 0.5 mg in 1 ml atthe selected temperature and pressure, for example, ambient temperatureand ambient pressure.

EXAMPLES

The examples set forth below are for illustrative purposes only and arein no way meant to limit the invention. The following examples are givento aid in understanding the invention, but it is to be understood thatthe invention is not limited to the particular materials or proceduresof examples.

Example 1

Synthesis of P(GA-co-CL)-b-PLLA Star Copolymer with End CappedRadiopaque Groups

The following example illustrates the synthesis of a multi-arm starcopolymer, PLLA-b-P(GA-co-CL) with radiopaque end groups. In thisexample the following are used: CL, GA, and LLA as monomers; stannousoctoate as catalyst; xylitol as initiator; and xylene as solvent. Theproposed synthesis is as follows:

Step 1: 30 g GA, 20 g CL, 0.5 g xylitol, and 100 ml xylene are addedinto a reactor free of moisture and oxygen.

Step 2: 100 mg stannous octoate are added after the temperature hasincreased to 100° C. The solution will become very viscous.

Step 3: Approximately 72 h later, 25 g LLA and 0.14 ml catalyst areadded.

Step 4: Approximately 48 h later, 100 ml xlyene, 20 ml of triethyl amineand 50 g trudobenzoyl chloride are added for 2 h esterificationreaction.

Step 5: The final product can be precipitated into methanol and dried ina vacuum oven overnight.

Example 2

Synthesis of P(GA-co-CL)-b-PLLA Star Copolymer with Radiopaque SideGroups and End Groups—Addition of Radiopaque Side Groups ontoP(GA-co-CL)-b-PLLA Star Copolymer with Radiopaque End Groups

-   -   Step 1: 100 g P(GA-co-CL)-b-PLLA star copolymer with radiopaque        end groups (from Example 1) is dissolved in 2 L anhydrous THF in        a reactor equipped with a mechanical stirrer and the solution is        kept at low temperature (−70° C.) under argon atmosphere.    -   Step 2: 300 mL lithium dilsopropyl amide solution in THF (2M/L)        is added into the reactor and the mixture is stirred for 1 h.    -   Step 3: 150 g iodine (in 200 mL THF) is added into the reactor        and the mixture is stirred for 2 h.    -   Step 4: The star copolymer with formed iodine side groups is        extracted with 5 L dichloromethane.    -   Step 5: The dichloromethane solvent is partially evaporated        under reduced pressure.    -   Then the concentrated star copolymer solution is precipitated        into 5 L methanol, filtered out, and dried under vacuum at        80° C. till constant weight.

Example 3

The following example illustrates the preparation of PLLA withradiopaque end group(s):

Step 1: Dissolve 500 g PLLA into 5 L xylene. Then add 13 ml of triethylamine and 40 g triidobenzoyl chloride for 2 h esterification reaction.

Step 2: The final product can be precipitated into methanol and dried ina vacuum oven overnight.

Example 4

The following example illustrates stent preparation from the blend ofPLLA/radiopaque block copolymer:

Step 1: A two layer tubing is formed by the coextrusion of aPLLA/radiopaque star block copolymer blend (100:10) as inner layer andradiopaque star block copolymer as outer layer. The thickness of innerlayer and the radiopaque outer layer is set to 0.05 inch and 0.005 inch,respectively. The ID of the extruded tubing is set to about 0.021 inchand the OD is about 0.076 inch.

Step 2: Expand the extruded tubing and cut into stent by laser.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A stent formed from a biodegradable polymer material, whereinradiopaque functional groups are chemically bonded to at least some ofpolymers of the polymer material.
 2. The stent of claim 1, wherein theradiopaque functional groups are selected from the group consisting ofiodine, triiodobenzoyl chloride, and triidobenzoic acid.
 3. The stent ofclaim 1, wherein the polymer material comprises an unbranched polymer.4. The stent of claim 1, wherein the polymer material comprises a starpolymer.
 5. The stent of claim 1, wherein the radiopaque functionalgroups are chemically bonded to the backbone of at least some of thepolymers of the polymer material,
 6. The stent of claim 5, wherein theradiopaque functional group is added by removal of a proton of amethylene group in an a position of an ester carbonyl on the backbone.7. The stent of claim 1, wherein the radiopaque functional groups arechemically bonded to end groups of at least some of the polymers of thepolymer material.
 8. The stent of claim 1, wherein the biodegradablepolymer material comprises a blend of an unbranched semi-crystallinepolymer and a star copolymer, wherein the radiopaque functional groupsare chemically bonded to the star copolymer.
 9. The stent of claim 1,wherein the polymers of the polymer material are selected from the groupconsisting of poly(L-lactide), poly(DL-lactide), polycaprolactone,polyglycolide, and copolymers thereof.
 10. An implantable medical devicecomprising structural elements fabricated at least in part from apolymer blend comprising: a biodegradable matrix polymer blended withbiodegradable linear block copolymers, the linear block copolymershaving a discrete phase segment and a continuous phase segment, whereinthe discrete phase segment is immiscible with the matrix polymer suchthat discrete phase segments form a discrete phase within the matrixpolymer, wherein the continuous phase segment is miscible with thematrix polymer, wherein radiopaque functional groups are chemicallybonded to the discrete phase segments, the continuous phase segments, orboth.
 11. The device of claim 10, wherein the implantable medical deviceis a stent.
 12. The device of claim 10, wherein the radiopaquefunctional groups are selected from the group consisting of iodine,triiodobenzoyl chloride, and triidobenzoic acid.
 13. The device of claim10, wherein the radiopaque functional groups are chemically bonded tothe ends of the continuous phase segments, the discrete phase segments,or both.
 14. The device of claim 10, wherein the radiopaque functionalgroups are chemically bonded along the backbone of the discrete phasesegments.
 15. The device of claim 14, wherein the radiopaque functionalgroup is added by removal of a proton of a methylene group in an aposition of an ester carbonyl on the backbone.
 16. The device of claim10, wherein the block copolymers are dispersed throughout the matrixpolymer.
 17. The device of claim 10, wherein the discrete phase segmentsare faster degrading than the continuous phase segments and the matrixpolymer.
 18. The device of claim 10, wherein the discrete phase segmentsare of the same or similar chemical composition as the matrix polymer.19. The device of claim 10, wherein the discrete phase segments have aTg below body temperature so that the discrete phase is elastic atphysiological conditions, and wherein the continuous phase segments andthe matrix polymer have a Tg above body temperature so that thecontinuous phase is glassy at physiological conditions.
 20. The deviceof claim 10, wherein the matrix polymer and the continuous phasesegments comprise PLLA.
 21. The device of claim 10, wherein the discretephase segments comprise units selected from the group consisting of CA,TMC, and dioxanone.
 22. The device of claim 10, wherein 1 to 20 wt % ofthe polymer blend comprises the linear block copolymer.
 23. The deviceof claim 10, wherein the structural elements comprise a first layercomprising the polymer blend and a second layer comprising a majority ofthe linear block copolymer including the radiopaque functional groupschemically bonded to the discrete phase segments, the continuous phasesegments, or both.
 24. An implantable medical device comprisingstructural elements fabricated at least in part from a polymer blendcomprising: a biodegradable matrix polymer blended with biodegradablestar-block copolymers, the star-block copolymers having at least threearms, wherein the arms include inner segments and outer segments, theinner segments being immiscible with the matrix polymer and forming adiscrete phase within the matrix polymer, wherein the outer segments aremiscible with the matrix polymer, wherein radiopaque functional groupsare chemically bonded to the inner segments or the outer segments. 25.The device of claim 24, wherein the implantable medical device is astent.
 26. The device of claim 24, wherein the radiopaque functionalgroups are selected from the group consisting of iodine, triiodobenzoylchloride and triidobenzoic acid.
 27. The device of claim 24,-wherein theradiopaque functional groups are chemically bonded to one or more of theends of the outer segments.
 28. The device of claim 24, wherein theradiopaque functional groups are chemically bonded along the backbone ofthe inner segments.
 29. The device of claim 28, wherein the radiopaquefunctional group is added by removal of a proton of a methylene group inan a position of an ester carbonyl on the backbone.
 30. The device ofclaim 24, wherein the star-block copolymers are dispersed throughout thematrix polymer.
 31. The device of claim 24, wherein the inner segmentsare faster degrading than the outer segments.
 32. The device of claim24, wherein the outer segments are of the same or similar chemicalcomposition as the matrix polymer.
 33. The device of claim 24, whereinthe inner segments have a Tg below body temperature so that the discretephase is elastic at physiological conditions, and wherein the outersegments and the matrix polymer have a Tg above body temperature so thatthe continuous phase is glassy at physiological conditions.
 34. Thedevice of claim 24, wherein the matrix polymer and the outer segmentscomprise PLLA.
 35. The device of claim 24, wherein the inner segmentscomprise units selected from the group consisting of CL, TMC, anddioxanone.
 36. The device of claim 24, wherein 1 to 20 wt % of thepolymer blend comprises the star-block copolymer.
 37. The device ofclaim 24, wherein the structural elements comprise a first layercomprising the polymer blend and a second layer comprising a majority ofthe star block copolymer including the radiopaque functional groupschemically bonded to the inner segments, the outer segments, or both.